There are numerous procedures available for the preparation of carboxylic esters from acid and hydroxyl components. However, the methods generally involve activation of either the acid (e.g. in the form of acyl halide) or the hydroxyl (e.g. as ester) component, which means introduction of an extra reaction step.
In the following, references to the literature are given by numbers within brackets. The numbers refer to literature sources listed after the examples.
During recent years carbodiimides, and especially N,N.sup.1 -dicyclohexylcarbodiimide (in the following abbreviated as DCC), have attracted increasing attention as condensing agents in ester synthesis (1, 2). Since both the acid and the hydroxyl compound are used as such in the reaction this synthesis has the obvious advantage of proceeding without the extra activation step of at least one reactant.
Esters of carboxylic acids with primary or secondary alcohols, as well as with phenols, are obtainable with this method (3). Tertiary alcohols generally react in only very low yield (3). However, the yield of ester is usually decreased by the simultaneous formation of an N-acylurea derivative as by-product, as illustrated below (4, 5). ##STR1##
This by-product may also cause problems in the work-up procedure and contaminate the desired ester. Numerous attempts have been made to increase the yield of ester by choosing reaction conditions so as to avoid the formation of the by-product. It has been found that the use of pyridine as solvent promotes the formation of ester (1, 6), although the appearance of smaller or larger quantities of N-acylurea usually cannot be avoided.
It has now, surprisingly, been found that addition of a strong acid to the pyridine solution considerably increases the yield of ester and decreases, or even prevents, the formation of the N-acylurea compound, and that the strong acid can be used in a catalytic amount. Table 1 shows that condensation of carboxylic acids with phenol and primary and secondary alcohols in pyridine with DCC in he presence of a catalytic amount of p-toluenesulfonic acid (in the following abbreviated as pTSA) gives excellent yields of ester, whereas reaction without said catalyst gives a much poorer result, due to the formation of the corresponding N-acylurea derivative.
As is seen in Table 1, the yield of ester is not particularly outstanding when tertiary alcohols are employed, even with pTSA added to the reaction mixture. However, the promoting effect of the acid catalyst on the ester formation is definitely evident even in this case.
Although the exact mechanism involved in the reaction is not fully understood, the fact that increased yields and purity of desired carboxylic acid esters are realized by the addition of the strong acid into the basic reaction mixture is indeed unexpected as, in fact, the addition of strong acid into the present basic esterification reaction mixture is not indicated by any known prior art for any purpose. In theory, the desirable result occurs due to suppression of side reactions, which is most likely due in some way or other to the presence of a salt between the pyridine and the strong acid, although once again the way in which this salt operates to suppress the undesired side reactions is not presently clear.
Table 1 ______________________________________ Reaction of a carboxylic acid, a hydroxyl compound, and DCC (molar ratio 1.0:1.1:1.2) in pyridine. (See examples 1 and 2 for experimental details.) ##STR2## ##STR3## (a) yield (%).sup.+ R with pTSA without pTSA ______________________________________ n-hexyl 95 40 i-propyl 98 5 t-butyl 8 0 phenyl 96 20 ______________________________________ ##STR4## ##STR5## (b) yield (%).sup.+ R.sup.2 with pTSA without pTSA ______________________________________ n-butyl 96 66 i-propyl 99 58 t-butyl 17 3 phenyl 93 39 ______________________________________ .sup.+ Several esterifications of benzoic acid using DCC as condensing agent are mentioned in the literature. Without any catalyst present methy benzoate has been prepared in a 60% yield using a large excess of methano (4), and phenyl benzoate has been obtained in a 12% yield from equimolar amounts of reactants (7).
Table 2 __________________________________________________________________________ Yield of steroid esters of carboxylic acids (See Examples 3,4, and 5 for experimental details.) yield (%).sup.+ ester with pTSA without pTSA __________________________________________________________________________ ##STR6## 85 74 ##STR7## 87 50 ##STR8## 89 73 __________________________________________________________________________ .sup.+ Calculated as pure compound
As is seen from Table 1, carboxylic esters are obtained in high yields from phenols and from primary and secondary alcohols when approximately equimolar amounts of the reacting carboxylic acid and hydroxyl compound are employed. Although the present invention is of general value for the preparation of esters, its main area of application will therefore be in the synthesis of esters of expensive starting materials, where the use of large excess of one reactant is highly uneconomical.
Steroid alcohols esterified with valuable carboxylic acids are one such type of esters which are preferably synthesized by the method of the present invention. This class of esters is of great pharmaceutical interest, e.g. as anticancer agents (14, 16) and as long-acting hormonal agents (15). Several steroid esters of carboxylic acids have now been prepared in pyridine using DCC as condensing agent. The catalytic effect of pTSA on the reactions is evident from the yields given in Table 2.
Other types of esters of great pharmaceutical interest which are prepared from expensive starting materials, and which may conveniently be synthesized by the method of the present invention, are for instance esters of penicillins, cephalosporins, prostaglandins, neuroleptics, and certain amino acids.
In the esterifications mentioned above, pTSA and DCC may be replaced by other strong acids and carbodiimides, respectively. Thus, the promoting effect on the formation of ester exerted by an acid catalyst in the presence of pyridine seems to be a general phenomenon when carbodiimides are used as condensing agents.